Anaplastic large-cell lymphomas (ALCL) carrying anaplastic lymphoma kinase (ALK) comprise a distinct clinical-pathological entity (Li et al, 2007, Med Res Rev 28(3):372-412; Wasik et al., 2009, Semin Oncol 36(2 Suppl 1):527-35; Tabbó et al, 2012, Front Oncol 2:41). ALK+ALCL are derived from CD4+ T lymphocytes, typically occur in children and young adults, and involve soft tissues and other extranodal sites. As the name implies, they are comprised of large highly atypical cells with prominent nuclei and abundant cytoplasm and, hence, bear little resemblance to their normal CD4+ T-cell counterparts, either resting or activated. They also display a unique phenotype with the variable loss of CD3 and other T-cell markers and strong expression of CD30; a cell surface receptor from the TNF-R family.
While ALK is physiologically expressed only in a subset of immature neuronal cells (Li et al, 2007, Med Res Rev 28(3):372-412), its aberrant expression has been identified in a subset of ALCL (Morris et al., 1994, Science 263(5151):1281-1284; Shiota et al., 1994, Oncogene 9(6):1567-1574) and, subsequently, in a spectrum of histologically diverse malignancies including subsets of a large B-cell lymphoma, inflammatory myofibroblastic tumor, non-small cell lung carcinoma (Li et al, 2007, Med Res Rev 28(3):372-412; Wasik et al., 2009, Semin Oncol 36(2 Suppl 1):S27-35; Tabbó et al, 2012, Front Oncol 2:41) and several other types of cancer. The aberrant expression of ALK typically results in these malignancies from chromosomal translocations involving the ALK gene and various partner genes with the nucleophosmin (NPM) gene being by far the most frequent partner in ALK+ALCL (Li et al, 2007, Med Res Rev 28(3):372-412) and EML4 in lung carcinoma (Soda et al., 2007, Nature 448:561-566). The NPM-ALK, EML4-ALK and other chimeric proteins are constitutively activated through autophosphorylation (Morris et al., 1994, Science 263(5151):1281-1284; Shiota et al., 1994, Oncogene 9(6):1567-1574) and highly oncogenic as documented mainly by using patient-derived cell lines and transgenic mouse models (Fujimoto et al., 1996, Proc Natl Acad Sci USA 93(9):4181-4186; Kuefer et al., 1997, Blood 90(8):2901-2910; Chiarle et al, 2003, Blood 101(5):1919-1927; Turner et al., 2006, Anticancer Res 26(5A):3275-3279; Giuriato et al., 2010, Blood 115(20):4061-4070). NPM-ALK acts by activating a number of signal transduction pathways such as STAT3 (Zhang et al., 2002, J Immunol 168(1):466-474; Zamo et al., 2002, Oncogene 21(7):1038-1047) and mTORC1 including its down-stream target S6RP (Marzec et al., 2007, Oncogene 26(38):5606-5614). The chronic activity of these signaling pathways leads to the persistent modulation of a number of genes and results in sustained cell proliferation, resistance to cell death, and other oncogenic properties. NPM-ALK is capable of fostering evasion of the anti-tumor immune response by inducing expression of potent immunosuppressive proteins: the cytokine IL-10 and the cell membrane bound ligand PD-L1/CD274 (Marzec et al., 2008, Proc Natl Acad Sci USA 105(52):20852-20857; Kasprzycka et al., 2006, Natl Acad Sci USA 103(26):9964-9969).
Cellular transformation by NPM-ALK has been demonstrated in immortalized rodent fibroblasts (Bai, R Y. et al. (1998) Mol Cell Biol. 18:6951-6961), and confirmed in studies which have shown that ALK protects Ba/F3 and PC12 cells from interleukin-3 or growth factor withdrawal (Stoica, G E., et al. (2001) J Biol. Chem. 276:16772-16779 and (Bai R Y., et al. (1998) Mol Cell Biol. 18:6951-6961). Transfer of NPM-ALK transduced bone-marrow cells into irradiated host recipient mice resulted in the generation in vivo of large cell B-cell lymphomas (Kuefer, M U. et al. (1997) Blood. 90:2901-2910). The later, even more refined studies using T-cell specific promoters resulted in the development of T-cell malignancies in the host mice (Chiarle et al. (2003) Blood 101:1919-1827). However, these tumors comprise of immature rather than mature T lymphocytes and lack key morphologic, phenotypic and other characteristics of human, patient-derived ALCL.
In the past few years, the molecular mechanisms of ALK-mediated cellular transformation have also been partially elucidated (Duyster, J. et al. (2001) Oncogene. 20:5623-5637). It has been shown that the ALK portion of the fusion protein, corresponding to the cytoplasmic tail of the ALK receptor and containing the catalytic domain, is absolutely required for transformation (Bai, R Y. et al. (1998) Mol Cell Biol. 18:6951-6961), whereas all the N-terminal regions of the ALK chimeras function as dimerization domains (Bischof, D. et al. (1997) Mol Cell Biol. 17:2312-2325) and (Duyster, J. et al. (2001) Oncogene. 20:5623-5637). As a result of spontaneous dimerization, ALK undergoes autophosphorylation and becomes catalytically active. Constitutively active ALK fusion proteins can bind multiple adaptor proteins and activate a series of pathways involved in cell proliferation, transformation and survival. These include the PLC-Shc PI3-K/Akt and the Jak3-Stat3 pathways (Bai, R Y. et al. (1998) Mol Cell Biol. 18:6951-6961; Bai R Y., et al. (2000) Blood. 96:4319-4327 and Zamo, A. et al. (2002) Oncogene. 21:1038-1047).
Given limitations of the existing mouse models and cell lines derived from patient tumors, there is a clear need to develop new models of ALK-driven malignancies. In addition, there are no good models to transform normal human cells including T lymphocytes and bronchial epithelial cells, ALCL and lung carcinoma are derived from, respectively. Thus, there is a need in the art for a model of transformation by ALK chimeras in primary normal cells. The present invention satisfies this need in the art.